The long-term objectives of this project involve the development of new synthetic strategies and the application of these strategies to the synthesis of complex systems of biological interest. In the AI program we hope to apply these capabilities to the synthesis of substances of interest as potential antibiotics, antiviral agents, or as antitumor drugs. In this next grant period we will focus on a broad range of chemical goals with diverse biological implications. A major and comprehensive effort is envisioned in the synthesis of oligosaccharides. We will study a potential menu of reactions whereby glycals will be substrates for electrophilically induced glycosidation. Included in this work are 2- deoxy, 2-halo, 2-amino, and "normal" 2-oxygenated oligosaccharides. The ultimate goal is the development of a capability in polymer based oligosaccharide construction. Specific targets in the carbohydrate area will be novel glycosides of avermectin and adriamycin, as well as the full carbohydrate portion of allosamidin. A study of the use of these concepts for the synthesis of novel nucleosides of interest in anti-AIDS therapy will be launched. Some new strategies in the synthesis of heterocycles have been developed. The application of these findings to the total synthesis of several key target systems will be pursued. Particularly interesting in this regard are castanospermine and FR900482. Castanospermine has been shown to have some anti-AIDS potential as an inhibitor of enzymes responsible for glycoprotein maturation. FR900482 has engendered considerable interest due to its very novel structure and reported "exceptionally potent" antitumor activity. We also will be directing a great deal of effort to the synthesis of esperamicin. Here the challenge goes beyond the complexity of the synthetic problem. Through suitable structures, which can be obtained uniquely through synthesis, a better understanding of the mode of action of this important antitumor agent will be achieved. A major effort will be directed toward the total synthesis of FK-506. This compound is the most powerful immunosuppressant now known (100 more active than cyclosporine). We will also continue our quinone- hydroquinone chemistry in the context of the biomimetic chemistry of adriamycin. Through these studies a superior insight into the mode of action of the antaracyclines will be sought. The completion of our efforts in the tunicamycin area is envisioned. At the present time the only remaining problem is the construction of the trehalose type of linkage.